This invention relates to treatment of schizophrenia and other psychotic disorders. This invention especially relates to treatment of schizophrenia and other psychotic disorders by enhancement of receptor functioning in synapses in brain networks responsible for higher order behaviors. In particular, the invention provides methods for the use of AMPA receptor up-modulators in conjunction with antipsychotics for the treatment of schizophrenia.
The release of glutamate at synapses at many sites in mammalian forebrain stimulates two classes of postsynaptic receptors. These classes are usually referred to as .alpha.-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/quisqualate and N-methyl-D-aspartic acid (NMDA) receptors. AMPA/quisqualate receptors mediate a voltage-independent fast excitatory post-synaptic current (the fast epsc) whereas NMDA receptors generate a voltage-dependent, slow excitatory current. Studies carried out in slices of hippocampus or cortex indicate that the AMPA receptor-mediated fast epsc is by far the dominant component at most glutamatergic synapses under most circumstances.
AMPA receptors are not evenly distributed across the brain but instead are largely restricted to telencephalon and cerebellum. These receptors are found in high concentrations in the superficial layers of neocortex, in each of the major synaptic zones of hippocampus, and in the striatal complex, as reported by Monaghan et al., in Brain Research 324:160-164 (1984). Studies in animals and humans indicate that these structures organize complex perceptual-motor processes and provide the substrates for higher-order behaviors. Thus, AMPA receptors mediate transmission in those brain networks responsible for a host of cognitive activities.
Schizophrenia is a chronic disease that is characterized by positive (hallucinations, delusions), negative (social withdrawal, flattened affect) and cognitive (formal thought disorder, executive memory dysfunction) symptoms. The dopamine hypothesis, that schizophrenia stems from excessive midbrain dopamine transmission, originated from studies with neuroleptics that revealed correlations between clinical efficacy, effects on dopamine metabolism (Carlsson & Lindqvist, Acta Pharmacol. Toxicol. 20:140-144, 1967) and binding to dopamine receptors (Creese et al., Science 192:481-482, 1976). In addition, drugs that increase synaptic dopamine concentration, (e.g., amphetamines) produce aberrant, stereotyped behavior in animals (WT McKinney, in SC Shultz and CA Tamminga (eds) Schizophrenia: Scientific Progress. Oxford University Press, New York, pp 141-154, 1989) and schizophrenia-like symptoms in humans (Snyder, Am. J Psychol. 130:61-67, 1976).
However, accumulating evidence suggests that schizophrenia may also be caused by reduced neocortical glutamatergic function. In vivo imaging studies have shown reduced metabolic activity (Andreasen et al., Lancet 349:1730-1734, 1997; Weinberger and Berman, Philos. Trans. R Soc. Lond. B Biol. Sci 351:1495-1503, 1996) in frontal and temporal cortices that are rich in glutamatergic (excitatory) synapses. Histopathologic studies have documented cytoarchitectural abnormalities (reviewed in Weinberger and Lipska, Schizophrenia Res. 16:87-110, 1995), as well as reduced neuron or synapse densities and reduced AMPA receptor (AMPA-R) densities in these same areas in post-mortem schizophrenic brain (Eastwood et. al., Biol. Psychiatry 41:636-643, 1997), including hippocampus (Breese et al., Brain Res. 674:82-90, 1995). This evidence is further supported by recent molecular studies that showed decreased AMPA-R subunit mRNA prevalence in neocortex (Eastwood et al., Mol. Brain Res. 29:211-223, 1995) and hippocampus of schizophrenic brains (Eastwood et. al., Mol. Brain Res. 44:92-98, 1997). Neurochemical studies have found reduced glutamate concentrations in cerebrospinal fluid (Kim et al., Neuroscience Letters 20:379-382, 1980) and lower glutamate and aspartate levels in prefrontal and temporolimbic areas (Tsai et al., Arch. Gen. Psychiatry 52:829-836, 1995). Finally, phencyclidine (PCP), ketamine and other use-dependent antagonists at NMDA-R produce aberrant behavior in animals (Freed et al., Psychopharmacology 71: 291-297, 1980), exacerbate symptoms in patients (Lahti et al., Neuropsychopharmacology 13:9-19, 1995), and produce a range of psychotic symptoms in volunteers that can accurately mimic symptoms of schizophrenic patients (Krystal et al., Arch. Gen. Psychiatry 51:199-214, 1994). Thus, significant recent evidence supports the `hypofrontality` hypothesis of reduced excitatory tone in fronto-temporal cortices of the schizophrenic brain.
For the reasons set forth above, drugs that enhance the functioning of AMPA receptors have significant benefits for the treatment of schizophrenia. See, e.g., U.S. application Ser. No. 08/521,022. Such drugs should also ameliorate the cognitive symptoms that are not addressed by currently-used antipsychotics. Experimental studies, such as those reported by Arai and Lynch, Brain Research, 598:173-184 (1992), indicate that increasing the size of AMPA receptor-mediated synaptic response(s) enhances the induction of long-term potentiation (LTP). LTP is a stable increase in the strength of synaptic contacts that follows repetitive physiological activity of a type known to occur in the brain during learning. Compounds that enhance the functioning of the AMPA form of glutamate receptors facilitate the induction of LTP and the acquisition of learned tasks as measured by a number of paradigms: Granger et al., Synapse 15:326-329 (1993); Staubli et al., PNAS 91:777-781 (1994); Arai et al., Brain Res. 638:343-346 (1994); Staubli et al., PNAS 91:11158-11162 (1994); Shors et al., Neurosci. Let. 186:153-156 (1995); Larson et al., J. Neurosci. 15:8023-8030 (1995); Granger et al., Synapse 22:332-337 (1996); Arai, et al., JPET 278:627-638 (1996); Lynch et al., Internat. Clin. Psychopharm. 11:13-19 (1996); Lynch et al., Exp. Neurology 145:89-92 (1997); Ingvar et al., Exp. Neurology 146:553-559 (1997); and Lynch and Rogers, WO 94/02475 (PCT/US93/06916).
There is a considerable body of evidence showing that LTP is the substrate of memory. For example, compounds that block LTP interfere with memory formation in animals, and certain drugs that disrupt learning in humans antagonize the stabilization of LTP, as reported by del Cerro and Lynch, Neuroscience 49:1-6 (1992). A possible prototype for a compound that selectively facilitates the AMPA receptor was disclosed by Ito et al., J. Physiol. 424:533-543 (1990). These authors found that the nootropic drug aniracetam (N-anisoyl-2-pyrrolidinone) increases currents mediated by brain AMPA receptors expressed in Xenopus oocytes without affecting responses by .gamma.-aminobutyric acid (GABA), kainic acid (KA), or NMDA receptors. Infusion of aniracetam into slices of hippocampus was also shown to substantially increase the size of fast synaptic potentials without altering resting membrane properties. It has since been confirmed that aniracetam enhances synaptic responses at several sites in hippocampus, and that it has no effect on NMDA-receptor mediated potentials. See, for example, Staubli et al., in Psychobiology 18:377-381 (1990) and Xiao et al., Hippocampus 1:373-380 (1991). Aniracetam has also been found to have an extremely rapid onset and washout, and can be applied repeatedly with no apparent lasting effects; these are valuable traits for behaviorally-relevant drugs. Unfortunately, the peripheral administration of aniracetam is not likely to influence brain receptors. The drug works only at high concentrations (.about.1.0 mM) and Guenzi and Zanetti, J. Chromatogr. 530:397-406 (1990) report that about 80% of the drug is converted to anisoyl-GABA following peripheral administration in humans. The metabolite, anisoyl-GABA, has been found to have only weak aniracetam-like effects.